Mechanisms for regulating the efficacy of synaptic coupling, or synaptic strength, between neurons are required for critical brain functions such as learning and memory. The process of altering synaptic strength between neurons, broadly termed synaptic plasticity, is impaired or absent in numerous neuropsychiatric disorders and diseases. A key mechanism for one of the most robust forms of synaptic plasticity, long-term potentiation, is the addition of AMPA-type neurotransmitter receptors from internal vesicular stores known as recycling endosomes (REs), to the postsynaptic membrane. Recent work has demonstrated that a large fraction of dendritic spines, the major sites of excitatory synaptic contact, contain REs and that these REs undergo fusion with the spine plasma membrane to deposit a stable pool of AMPA receptors at or near the synapse in response to plasticity-inducing activity. These data indicate that spine REs are poised for local delivery of plasticity factors to activated synapses, but many fundamental questions remain. For example, why these organelles are found in some spines but not others, how they are mobilized to fuse with the plasma membrane by plasticity-inducing stimuli, and how fusion contributes to synaptic function and plasticity are important issues we propose to address in this project. In Aim1 we will address whether the history of synaptic activity influences the distribution REs at individual synapses and/or their AMPA receptor content. In Aim2 we will determine whether plasticity at individual synapses directly scales with spine RE content. In Aim3 we will dissect the second messengers and signaling molecules that couple synaptic activity to spine RE fusion. Combined, these independent but complementary aims will greatly advance our understanding of fundamental forms of neuronal plasticity and inform future efforts in determining how and why plasticity is disrupted in numerous neuropsychiatric disorders and diseases including Alzheimer's, autism, schizophrenia and addiction.